Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland Pfizer-Universidad de Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada 18016, Spain.
Mol Biol Cell. 2014 Jan;25(1):184-95. doi: 10.1091/mbc.E13-06-0306. Epub 2013 Nov 6.
Epithelial cell differentiation and polarized migration associated with epithelial-to-mesenchymal transition (EMT) in cancer requires integration of gene expression with cytoskeletal dynamics. Here we show that the PDZ-LIM domain protein PDLIM2 (Mystique/SLIM), a known cytoskeletal protein and promoter of nuclear nuclear factor κB (NFκB) and signal transducer and activator of transcription (STAT) degradation, regulates transcription factor activity and gene expression through the COP9 signalosome (CSN). Although repressed in certain cancers, PDLIM2 is highly expressed in invasive cancer cells. Here we show that PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype. This is accompanied by altered activity of several transcription factor families, including β-catenin, Ap-1, NFκB, interferon regulatory factors, STATs, JUN, and p53. We also show that PDLIM2 associates with CSN5, and cells with suppressed PDLIM2 exhibit reduced nuclear accumulation and deneddylation activity of the CSN toward the cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. Thus PDLIM2 integrates cytoskeleton signaling with gene expression in epithelial differentiation by controlling the stability of key transcription factors and CSN activity.
上皮细胞分化和极化迁移与癌症中的上皮-间充质转化 (EMT) 相关，需要将基因表达与细胞骨架动力学整合。在这里，我们表明 PDZ-LIM 域蛋白 PDLIM2（神秘/SLIM），一种已知的细胞骨架蛋白和核因子 κB（NFκB）和信号转导和转录激活因子（STAT）降解的启动子，通过 COP9 信号体（CSN）调节转录因子活性和基因表达。尽管在某些癌症中受到抑制，但 PDLIM2 在侵袭性癌细胞中高度表达。在这里，我们表明 PDLIM2 的抑制导致定向迁移丧失、无法极化细胞骨架以及 EMT 表型的逆转。这伴随着几个转录因子家族的活性改变，包括β-catenin、Ap-1、NFκB、干扰素调节因子、STATs、JUN 和 p53。我们还表明 PDLIM2 与 CSN5 相关，并且抑制 PDLIM2 的细胞表现出核积累减少和 CSN 对 cullin-RING 泛素连接酶的 cullin 1 和 cullin 3 亚基的去泛素化活性降低。因此，PDLIM2 通过控制关键转录因子的稳定性和 CSN 活性，将细胞骨架信号与上皮分化中的基因表达整合在一起。
